Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[CH:10]=[CH:11][N:12]2[C:17]=1[CH:16]=[CH:15][C:14]([O:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[N:13]2.[CH3:28][CH2:29][CH2:30]C[Sn](/C=C/C)(CCCC)CCCC>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][C:14]1[CH:15]=[CH:16][C:17]2[N:12]([CH:11]=[CH:10][C:9](=[O:27])[C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:28]=[CH:29]/[CH3:30])[N:13]=1
Reactant: C/C=C/[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1ccn2nc(Oc3ccc(F)cc3F)ccc2c1-c1ccccc1Br
Product: C/C=C/c1ccccc1-c1c(=O)ccn2nc(Oc3ccc(F)cc3F)ccc12

Procedure:
The title compound was prepared from 5-(2-bromophenyl)-2-(2,4-difluorophenoxy)-6H-pyrido[1,2-b]pyridazin-6-one as described in Example-7 using tri-N-butyl(1-propenyl)tin in place of tri-N-butyl (vinyl)tin. 50/50 mixture of cis and trans.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH2:15]([Br:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br-:22].[CH2:15]([N+:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc(OCC2CCOCC2)ccn1
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: [Br-]
Product: c1ccc(C[n+]2ccc(OCC3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
4-(Tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.1 g) was mixed with THF (12 ml), and benzyl bromide (1.4 g) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 1-benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25][CH3:26])=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:35]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1cccc(OC)c1
Yield: 19.3 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-hydroxybenzoate (0.805 g, 2.14 mmol) was dissolved in methylene chloride (50 ml) and after adding thereto in sequence copper acetate (0.429 g, 2.36 mmol), 3-methoxyphenylboronic acid (0.651 g, 4.28 mmol), Molecular Sieves 4A (0.500 g), triethylamine (0.541 g, 5.35 mmol) and pyridine (0.423 g, 5.35 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.200 g, 0.414 mmol, 19%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.01 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone described in Preparation Example R-4 (753 mg, 3.31 mmol) was dissolved in toluene (15 mL), and the solution was refluxed for 40 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water and ethyl acetate were added thereto, the organic layer was partitioned, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (260 mg, 1.32 mmol, 44%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]COC(C)=O.CCCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (2S,3S)—N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine (4.7 g, 14.26 mmol) in THF (70 mL) at −78° C. was added dropwise MeMgBr (3.0 M in THF, 23.8 mmol). The reaction was stirred at −78° C. for 3 h and TLC (20% EtOAc/hexane) showed complete reaction. The reaction was quenched by the addition of HOAc (5.0 mL) at −78° C., warmed to rt and diluted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification by flash chromatography (120 g ISCO silica gel column, 0-30% EtOAc/hexane) provided 80A-a (760 mg) and 80A-b (1.54 g) as colorless oil. 80A-a: For (20% EtOAc/hexane) 0.29. 80A-b: For (20% EtOAc/hexane) 0.25.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cccc2c1-c1ccccc1C2

Procedure:
A partial solution of 196.2 mg (1 mmol) of 4-hydroxy-fluoren-9-one in 2 mL EtOAc and 3 mL EtOH with 40 mg 10% Pd/C was stirred under a balloon of hydrogen for 27.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated. The residue was purified by plate layer chromatography with CH2Cl2-EtOAc(50:1) to give 102.7 mg of the title substance.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:26]1([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[CH:26]1([O:31][C:32](=[O:37])[C:33]([NH:34][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)([CH3:35])[CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CC(C)(N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NC(C)(C)C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.3 %

Procedure:
To a solution of N-Boc-piperidinone (2.00 g, 10.0 mmol) in dichloroethane (25 mL) was added α,α-dimethylglycine cyclopentyl ester tosylate (3.97 g, 11.6 mmol) and sodium triacetoxyborohydride (4.248 g, 20.0 mmol). The mixture was stirred at room temperature for 22 hours then poured into ethyl acetate (300 mL). The organic layer was washed with water (3 times 100 mL), dried (MgSO4) and concentrated to yield the desired product (3.556 g, 84% yield) which was carried forward without further purification. LC/MS: m/z 355.25 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OCC)(=O)[CH3:22].Cl>[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:21][CH3:22])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-t-hutoxycarbonyl-L-tyrosine (II, EXAMPLE 1, (235 g, 835 mmol) is dissolved in sodium hydroxide (4N, 705 mL) at 20-25°. Diethyl sullate (210 mL, 1.60 mol) is added over 15-20 min. The reaction mixture is stirred for 2 hr, then it is cooled with ice-bath (internal temperature around 15°). Ethyl acetate (1400 mL) is added, followed by slow addition ot hydrochloric acid (3N, 1410 mL) for 1 hr. The ethyl acetate layer is separated, and the aqueous layer is extracted with ethyl acetate (1400 mL). The ethyl acetate phase is concentrated to about 200 mL, then hexane (1600 mL) is added. The mixture is stirred in an ice-bath for 2 hr, filtered, washed with hexane (800 mL) in 3 portions. The precipitate is dried to give the title compound. The filtrate is concentrated, suspended in ethyl acetate/hexane (80/450 mL) for 2 hr, filtered and washed with hexane (250 mL) in 3 portions and dried to give additional title compound, NMR (MeOH-d4) δ7.11, 6.80, 4.22, 4.05, 3.08, 2.86 and 1.36; CMR δ175.4, 159.3, 157.8, 131.3, 130.4. 115.4, 80.5, 64.4, 56.4, 37.9, 28.7 and 15.2.
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(N(CC)CC)C>C(Cl)Cl>[N:25]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:22][CH3:23])=[O:24])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccc(C(=O)NC)cc2)cn1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1ccc(-c2ccc(C(=O)NC)cc2)cn1)n1ccnc1
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A mixture of 1-(5-(4-(methylcarbamoyl)phenyl)pyridin-2-yl)propyl methanesulfonate (0.02 g, 0.057 mmol), 1H-imidazole (0.008 g, 0.114 mmol) and triethylamine (0.03 mL, 0.114 mmol) in DCM (10 mL) was stirred and refluxed at 50° C. for 3 h. The mixture was then cooled to room temperature, poured out into ice water (50 mL) and extracted with DCM (2×50 mL). The organic layer was separated, dried (Na2SO4), and the solvent was evaporated under vacuo. The resulting residue was purified by preparative TLC using 5% methanol in dichloromethane and the product isolated as off white solid (0.007 g, 39% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.91 (d, 1H), 8.46 (d, 1H), 8.12 (d, 1H), 7.91 (d, 2H), 7.80 (d, 3H), 7.39 (d, 1H), 7.31 (s, 1H), 6.89 (s, 1H), 5.37 (t, 1H), 2.78 (d, 3H), 2.27 (m, 2H), 0.89 (t, 3H). LC-MS: m/z 321.5 [M+H]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:19]OS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[OH2:33]>CO.CC#N>[C:1]1([S:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)(=[O:19])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])OO
Reactant: O
Reactant: O=C1CCCc2cc(Sc3ccccc3)ccc21
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 72.27 %

Procedure:
A solution of 6-phenylsulfanyl-3,4-dihydro-2H-naphthalen-1-one (8.05 g, 31.65 mmol) in MeOH/MeCN (50 mL of each) was stirred at room temperature. OXONE™ (potassium peroxymonosulfate, 77.83 g, 126.60 mmol) was dissolved in 50 mL of water and was added to the stirring reaction. The reaction mixture was stirred for 15 hours, and then evaporated under reduced pressure. The resulting aqueous residue was diluted with 500 mL of water and extracted three times with 300 mL of EtOAc. The combined extracts were washed with water, saturated brine, and dried over MgSO4. The solvent was removed under reduced pressure to yield an oil which was eluted through silica gel with hexane followed by chloroform. Removal of solvent under reduced pressure afforded 6.55 g (22.87 mmol, 72.27%) of 6-benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one as a white solid, which was recrystallized from EtO2/hexanes. MS: 287 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=C(C(O)=O)[CH:2]=1.OS(O)(=O)=O.[C:18]([O:21][CH2:22]C)(=[O:20])[CH3:19].[CH3:24]CCCCC>CO>[CH3:24][O:9][C:7]([C:5]1[CH:6]=[N:1][CH:2]=[C:19]([C:18]([O:21][CH3:22])=[O:20])[CH:4]=1)=[O:8]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: CCCCCC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cncc(C(=O)OC)c1

Procedure:
3,5-Pyridinedicarboxylic acid (1.5 g, 63 mmol) and conc. H2SO4 (0.9 mL) in MeOH (15 mL) are heated in a microwave oven at 120° C. for 2 h. The solvent is evaporated to give a residue with is partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase is washed with brine, dried over Na2SO4, filtered and evaporated to give a light yellow solid. MS (LC-MS): 196 [M+H]+ TLC, Rf (ethyl acetate/hexane 1:1)=0.56.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.C1COCC1.[Cl-].[NH4+].O>CO.[Zn]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc([N+](=O)[O-])cc2)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
To a suspension of [6-chloro-3-methyl-4-(4-nitro-phenyl)-naphthalen-2-yl]-acetic acid methyl ester (133 mg, 0.36 mmol) in methanol (2 mL) was added THF (2 mL). Then, zinc dust (192.1 mg, 2.9 mmol) and ammonium chloride (192.6 mg, 3.6 mmol) were added followed by water (0.9 mL). The reaction mixture was stirred at room temperature for 10 minutes and TLC analysis of the mixture indicated the absence of starting material. The resulting solids were filtered and washed with ethyl acetate (20 mL). The solution was concentrated to remove organic solvent, then diluted with water (20 mL) and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (120 mg, 97.9%) as a light brown oil which solidified slowly. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.90 (d, J=8.7 Hz, 1 H), 7.79 (s, 1 H), 7.43 (dd, J=8.7, 1.9 Hz, 1 H), 7.27 (d, J=1.9 Hz, 1 H), 6.85 (d, J=8.2 Hz, 2 H), 6.72 (d, J=8.2 Hz, 2 H), 5.26 (s, 2 H), 3.93 (s, 2 H), 3.64 (s, 3 H), 2.09 (s, 3 H). HRMS calcd. for C20H18ClNO2 [(M+H)+] 340.1099, obsd. 340.1097.
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.S(Cl)([Cl:15])=O>>[S:1]1[C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2c(s1)CCCC2
Product: O=C(Cl)c1cc2c(s1)CCCC2

Procedure:
1.0 g of 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid was reacted with 4 ml of thionyl chloride for 3.5 hours under reflux. Then, excess thionyl chloride was distilled off under reduced pressure to obtain 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[N:31][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]2)=[N:33][CH:34]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH:36]3[CH2:41][CH2:40][CH:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:33][CH:34]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: CCOC(=O)C1CCC(Oc2ncc(Br)cn2)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Oc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)cn2)CC1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.396 mmol), ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate (130 mg, 0.396 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.026 g, 0.032 mmol), 1,4-dioxane (3.6 mL), water (0.36 mL), and aqueous sodium carbonate (2 M, 0.396 mL, 0.791 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes using a microwave reactor. The resulting suspension was diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford ethyl 4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylate as a mixture of cis and trans isomers. MS ESI calc'd. for C25H27F3N5O3 [M+H]+ 502. found 502.
Reaction SMILES: [C:1](N[C@H](C(O)=O)CS)(=O)[CH3:2].O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1([SeH-](C2C=CC=CC=2)=[Se])C=CC=CC=1.[O:63]1[CH:69]2[CH:64]1[C:65](=[O:74])[CH:66]1[CH:68]2[C:67]1([F:73])[C:70]([O-:72])=[O:71]>O.C(O)C.O.O1CCCC1>[F:73][C:67]1([C:70]([O:72][CH2:1][CH3:2])=[O:71])[CH:66]2[CH:68]1[CH:69]([OH:63])[CH2:64][C:65]2=[O:74]
Reactant: O=C1C2OC2C2C1C2(F)C(=O)[O-]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [Se]=[SeH-](c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)C2C(=O)CC(O)C21
Temperature: 38 °C
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, 23.2 g of N-acetyl-L-cystein, 54.3 g of sodium tetraborate decahydrate and 0.7 g of diphenyldiselenide were suspended in 450 ml of a water-ethanol (1:1) mixture solution which had been deaerated. 9.5 g of (1RS,3RS,4RS,5SR,6RS)ethyl (3,4-epoxy-6-fluoro-2-oxobicyclo [3.1.0]hexane-6-carboxylate dissolved into 225 ml of tetrahydrofuran was added thereto, and this was stirred at room temperature for one day, at 38° C. for 12 hours, and at 85° C. for 5 hours. After the reaction solution was cooled down to room temperature, it was poured into water and extracted three times with diethyl ether. The obtained organic layers were consolidated and dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=3:1 to 1:1), yielding 3.9 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]#[N:16].Br[CH2:18][CH2:19][O:20][CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COCCBr
Reactant: N#Cc1cc(-c2ccc(O)cc2)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccc(F)c(C#N)c2)cc1

Procedure:
A mixture of 4-fluoro-4′-hydroxy-1,1′-biphenyl-3-carbonitrile (0.50 g, 2.35×10−3 mol), 1-bromo-2-methoxyethane (0.33 g, 2.35×10−3 mol), potassium iodide (0.04 g, 2.35×10−4 mol) and potassium carbonate (1.30 g, 9.40×10−3 mol) in butanone (20 cm3) was reacted, worked up and purified as described for compound 3 in Example 2. Yield 0.26 g (40%), GC purity (100%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 22 °C
Reaction time: 19 h
Yield: 80.5 %

Procedure:
Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[CH2:2][CH2:3][CH3:4].[CH2:17]([O:19][C@H:20]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](O)=[O:29])=[CH:24][CH:23]=1)[CH3:18].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16])[C:28](=[O:29])[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@H:20]([O:19][CH2:17][CH3:18])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23 g, 5.5 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0° C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 (3×100 mL), 5% HCl (3×100 mL), and brine (100 mL), dried over Na2SO4, and concentrated in vacuo. Purification on silica gel (120 g) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.07 g (43%) of a pale yellow oil.